This invention provides compounds which act upon the mammalian 5-HT1A receptor and methods for their use in treating, preventing or ameliorating diseases associated therewith, including anxiety, depression, enhancement of antidepressant activity, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer""s Disease, stroke/cerebral ischemia, nausea and vomiting, and in the treatment of prostate cancer and for use in promoting smoking cessation.
Compounds having selective partial agonist activity at the 5-HT1A receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone, Buspar(copyright), U.S. Pat. No. 3,717,634). 5-HT1A agonists and antagonists may find use in the treatment of several diseases such as anxiety, depression, enhancement of antidepressant activity, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer""s Disease, stroke/cerebral ischemia, nausea and vomiting, and in the treatment of prostate cancer and smoking cessation (for reviews, see: K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT1A Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995); L. E. Schechter and M. G. Kelly, An overview of 5-HT1A Receptor Antagonists: Historical Perspective and Therapeutic Targets, in Current Drugs Serotonin ID Research Alert, 2, 299-309 (1997)).
5-HT1A Agonists/Partial Agonists
Anxietyxe2x80x94The role of serotonin in anxiety has been well established (S. D. Iversen, Neuropharmacol., 23, 15530 (1984); J. E. Barrett and K. E. Vanover, Psychopharmacol., 112, 1 (1993)). 5-HT1A partial agonists and full agonists have demonstrated anxiolytic activity in both preclinical animal models of anxiety (R. J. Rogers, et al., Pharmacol. Biochem. Behav., 48, 959 (1994), P. F. Curle, et al., Drug Dev. Res., 32, 183 (1994); S. E. File and N. Andrews, Behav. Pharmacol., 5, 99 (1994)) and in clinical trials for anxiety (D. S. Chaney, et al., Ann. Rev. Med., 41, 437 (1990); R. D. Chiaie, et al., J. Clin. Psychopharamacol., 15, 12 (1995); L. D. Bedford. Abstracts. Am. Coll. Neuropsycho-pharmacol., San Juan, Puerto Rico, 167 (1994); H. G. M. Westenberg and J. A. Den Boer, Pharmacopsychiatry, 26, 30 (1993)).
Depressionxe2x80x94There is evidence that 5-HT1A agonists and high-efficacy partial agonists possess antidepressant activity (J. De Vry, Drug and News Perspectives, 9, 270 (1996)). This activity is thought to be the result of the drug""s ability to exert agonist activity on post-synaptic receptors and desensitize pre-synaptic autoreceptors. Buspirone showed weak antidepressant activity and flexinoxan, a 5-HT1A full agonist, entered clinical trials for depression (A. Sambunaris, et al., J. Clin. Psychiatry, 58 (suppl 6), 40 (1997)).
Nausea and Vomitingxe2x80x94Animal studies have shown that 5-HT1A agonists are effective antiemetics against a broad spectrum of conditions, including motion sickness and xylazine- and cis-platinin-induced vomiting (J. B. Lipcot and G. H. Crampton, Pharmacol. Biochem. Behav., 33, 627 (1989)). Flesinoxan, a 5-HT1A full agonist, was found to be particularly active in these models (J. B. Lipcot, Eur. J. Pharmacol., 253, 53 (1994)).
Stroke/Cerebral Ischemiaxe2x80x94Glutamate is a predominant neurotransmitter in the central nervous system and has been associated with the ischemia-induced pathophysiology seen in both acute neurodegenerative disorders such as stroke, transient ischemic attack, fetal hypoxia and spinal/brain trauma, and chronic neurodegenerative disorders such as epilepsy, Alzheimer""s Disease, amyotrophic lateral sclerosis, Huntingdon""s Disease, Parkinson""s Disease, AIDS dementia and retinal diseases (W. F. Holt, et al., Glutamate in Health and Disease: The Role of Inhibitors, In Neuroprotection in CNS Diseases, P. R. Bar and M. F. Beal, eds., Marcel Dekker, Inc., News York, 1997, pp. 87-119). Therefore, compounds which inhibit or attenuate the release of glutamate represent potential neuroprotective agents. Cerebral ischemia can also result from surgery where the blood flow must be halted for a period of time (e.g., coronary bypass surgery) due to the resulting anoxia and hypoglycemia (J. E. Arrowsmith, et al., A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients, Stroke, 29, 2357 (1998)). Compounds which inhibit or attenuate glutamate release would be expected to provide neuroprotection in these scenarios as well.
Serotonin 5-HT1A receptors are located in brain areas which are highly sensitive to ischemia, such as the hippocampus and cerebral cortex. It has been demonstrated that 5-HT1A receptor agonists and partial agonists are able to attenuate glutamate release, most likely through activation of 5-HT1A receptors located on glutamatergic terminals (S. Matsuyama, et al., Regulation of Glutamate Release via NMDA and 5-HT1A Receptors in Guinea Pig Dentate Gyrus, Brain Res., 728, 175 (1996)), and that a number of 5-HT1A agonists and partial agonists exert neuroprotective properties in vivo in animal models (J. De Vry, et al., BAYx3702, Drugs of the Future, 22, 341 (1997) and references cited within).
Therefore, compounds Which possess serotonin 5-HT1A agonist or partial activity may be useful as neuroprotective agents for the prevention and/or treatment of ischemia-induced brain damage resulting from acute conditions such as stroke, transient ischemic attack, fetal hypoxia, prolonged cardiac surgery and spinal/brain trauma as well as chronic conditions such as epilepsy, Alzheimer""s Disease, amyotrophic lateral sclerosis, Huntingdon""s Disease, Parkinson""s Disease, AIDS dementia and retinal diseases.
5-HT1A Antagonists
Anxietyxe2x80x94While no clinical trial results have been published, 5-HT1A antagonists have demonstrated anxiolytic activity in several animal models, most notably the elevated plus-maze (D. J. Bill and A. Fletcher, Br. J. Pharmacol., 111, 151P (1994); J.-L. Moreau, et al., Brain Res. Bull., 29, 901 (1992)) and the light/dark box (R. J. Rodgers and J. C. Cole, Eur. J. Pharmacol., 261, 321 (1994). Therefore, 5-HT1A antagonists may find use as anxiolytic agents.
Enhancement of Antidepressant Activityxe2x80x94The 5-HT1A receptor appears to play a major role in mediating antidepressant response (J. F. Deakin, et al., Trends Pharmacol. Sci., 14, 263 (1993). The delay in onset of antidepressant activity seen with serotonin-specific release inhibitors (SSRI""s) is a result of the activation of somatodendritic 5-HT1A autoreceptors and a resulting decrease in serotonin release (S. Hjorth and S. B. Auerbach, Behav. Brain Res., 73, 281 (1996). Chronic administration of the SSRI leads to an eventual desensitization of the 5-HT1A autoreceptor, an increase in neuronal firing and serotonin release and concomitant antidepressant activity.
Co-administration of a 5-HT1A antagonist would be expected to inhibit the SSRI-induced activation of pre-synaptic autoreceptors and, thus, hasten the onset of antidepressant action of SSRI""s. This hypothesis is supported by results from studies in animal models using more- or less-specific 5-HT1A antagonists in combination with SSRI""s (K. Briner and R. C. Dodel, Cur. Pharm. Des., 4, 291 (1998), and references cited within). Furthermore, clinical trials have shown that co-administration of the 5-HT1A antagonist pindolol significantly reduced the median time needed to achieve a sustained antidepressant response with the SSRI""s paroxetine (M. B. Tome, et al., Int. Clin. Psy., 12, 630 (1997) and fluoxetine (V. Perez, et al., Lancet, 349, 1594 (1997).
Therefore, 5-HT1A antagonists are expected to enhance the antidepressant activity of SSRI""s by reducing the delay in onset of action seen with this class of drugs.
Prostate Cancerxe2x80x94In addition to its role as a neurotransmitter, serotonin can function as a growth factor. Serotonin is found in most neuroendocrine cells of the human prostate, where it may play a role in the progression of prostate carcinoma (P. A. Abrahamsson, et al., Pathol. Res. Pract., 181, 675 (1986); N. M. Hoosein, et al., J. Urol., 149, 479A (1993)). The 5-HT1A antagonist pindobind has shown antineoplastic activity when tested against the human prostate tumor cell lines PC3, DU-145 and LNCaP in vitro and inhibited the growth of the aggressive PC3 cell line in vivo in athymic nude mice (M. Abdul, et al., Anticancer Res., 14, 1215 (1994).
Schizophreniaxe2x80x94Evidence has accumulated over the last decade to suggest that serotonin and various serotonin receptors play a role in the pathophysiology and pharmacological treatment of schizophrenia. Both receptor binding studies (T. Hashimoto, et al., Life Sci., 48, 355 (1991)) and autoradiography (J. N. Joyce, et al., Neuropsychopharmacol., 8, .315 (1993); P.W. J. Bumet, et al., Neuropsychopharmacol., 15, 442 (1996)) on postmortem brains of schizophrenia patients indicate that there is an increase in 5-HT1A receptor density. While the most efficacious antipsychotic treatments to date have targeted dopaminergic neurotransimission, it is clear from binding results that atypical antipsychotics also possess significant serotonergic affinity (H. Y. Meltzer, Clin. Neurosci., 3, 64 (1995). Notably, the 5-HT1A receptor has been associated with changes in dopaminergic neurotransmission (M. Hamon, et al., J. Pharmacol. Exp. Ther., 246, 745 (1988); L. E. Schechter, et al., J. Pharmacol. Exp. Ther., 255, 1335 (1990)). Furthermore, dysfunctional glutamatergic path ways appear to be involved in psychotic pathology and decreased glutamate levels have been demonstrated in schizophrenic brains (K. Q. Do, et al., J. Neurochem., 65, 2652 (1995); G. C. Tsai, et al., Arch. Gen. Psychiatry, 52, 829 (1995)). Thus, by enhancing glutamate availability and transmission, 5-HT1A antagonists may function as antipsychotic agents.
Cognitive Deficits from Alzheimer""s Diseasexe2x80x94Studies on the cholinergic deficits observed in Alzheimer""s Disease have made it apparent that not all patients can be characterized by deficits in this in this system alone (P. T. Francis, et al., Neurotransmitters and Neuropeptides, in Alzheimer""s Disease, R. D. Terry, ed., Raven Press, Ltd., New York, pp. 247-261 (1994)). More recent studies reveal that glutamatergic function is also severely disrupted. Glutamate is an important neurotransmitter that can enhance cognition and physiological phenomena such as long-term potentiation (LTP), which appears to play a role in mediating learning and memory processes. The activation of glutamatergic neurotransmission facilitates memory (U. Stabil, et al., PNAS (USA), 91, 777 (1994)), while glutamate antagonists impair learning and memory as well as LTP in rats (R. G. Morris, et al., Nature, 319, 774 (1986); T. V. Bliss and G. L. Collinridge, Nature, 361, 31 (1993)).
Studies on the post-mortem brains of Alzheimer""s patients have demonstrated reductions in glutamate receptors in both neocortex and hippocampus (J. T. Greenmyre, Arch. Neurol., 43, 1058 (1986); W. F. Marangos, et al., Trends Neurosci., 10, 37 (1987)). Rich in glutamatergic neurons, the pyramidal cell layer of the entorhinal cortex is one of the first areas in the Alzheimer""s brain to develop the morphological hallmarks of Alzheimer""s Disease, plaques and tangles. Furthermore, there are reduced levels of glutamate in the perforant pathway which projects from the entorhinal cortex to the dentate gyrus (B. T. Hyman, et al., Ann. Neurol., 22, 37 (1987)) and a loss of glutamate staining in the perforant path terminal zone that has been associated with Alzheimer""s Disease (N. W. Kowal and M. F. Beal, Ann. Neurol., 29, 162 (1991)). Thus, there is compelling evidence that a deficit in glutamatergic neurotransmission is associated with cognitive impairment and is a pathological finding in Alzheimer""s Disease.
Data indicate that 5-HT1A antagonists have a facilitatory effect on glutamatergic neurotransmission (D. M. Bowen, et al., Trends Neurosci., 17, 149 (1994)). Serotonin 5-HT1A antagonists have been shown to both potentiate NMDA-induced glutamate release from pyramidal neurons and significantly elevate glutamate release when administered alone (S. N. Dilk, et al., Br. J. Pharmacol., 115, 1169 (1995)). They inhibit the tonic hyperpolarizing effect of serotonin on neurons in both the cortex and hippocampus, which in turn enhances glutamatergic neurotransmission and signaling (R. Araneda and R. Andrade, Neuroscience, 40, 399 (1991)). Coupled with the observation that a functionally hyper-responsive serotonin system in Alzheimer""s Disease may contribute to the cognitive disturbances (D. M. McLoughlin, et al., Am. J. Psychiatry, 151, 1701 (1994)), the data suggest that 5-HT1A antagonists may improve cognition by removing the inhibitory effects of endogenous serotonin on pyramidal neurons and enhancing glutamatergic activation and the ensuing signal transduction.
Nevertheless, the cholinergic system clearly plays a role in cognitive processing, and recent therapies designed to improve cognition in Alzheimer""s patients have been targeted at enhancing cholinergic neurotransmission, either through inhibition of acetylcholinesterase or by the use of agonists. Postsynaptic M1 muscarinic acetylchloline receptors are located on pyramidal neurons along with glutamatergic and 5-HT1A receptor sites. In this regard, blockade of 5-HT1A receptors may compensate for the loss of cholinergic excitatory input by enhancing glutamatergic transduction through the same pathway. In fact, muscarinic (M1) signal transduction may be facilitated by blocking the hyperpolarizing action of serotonin. In addition, there is evidence that 5-HT1A receptor antagonists may decrease the formation of xcex2-amyloid plaques and tangles via its enhancement of muscarinic M1 receptor signaling and resulting activation of protein kinase C (J. D. Baxbaum, et al., PNAS (USA), 90, 9195 (1993)).
Preclinical evidence for treating Alzheimer""s Disease has been established using available 5-HT1A antagonists. WAY-100635 reversed the cognitive deficits induced by fornix lesions in marmosets (J. A. Harder, et al., Psychopharmacol., 127, 245 (1996)). WAY-100135 prevented the impairment of spatial learning caused by intrahippocampal scopolamine, a muscarinic antagonist (M. Carli, et al., Eur. J. Pharmacol., 283, 133 (1995)). NAN-190 has been shown to augment LTP (N. Sakai and C. Tanaka, Brain Res., 613, 326 (1993)). Taken together with the various in vitro data described above and in the literature, these studies strongly suggest that treatment with 5-HT1A receptor antagonists represent a viable strategy for restoring the multiple deficits associated with Alzheimer""s Disease.
Smoking Cessationxe2x80x94Cessation from chronic use of nicotine or tobacco in humans results in withdrawal symptoms, including anxiety, irritability, difficulty concentrating and restlessness. These withdrawal symptoms have been shown to play an important role in relapse (J. R. Hughes and D. Hatsukami, Arch. Gen. Psychiatry, 43, 289 (1986)). Preclinical evidence indicates that withdrawal from the chronic administration of nicotine increases the sensitivity of 5-HT1A receptors (K. Rasmussen and J. F. Czachura, Psychopharmacology, 133, 343 (1997)) and enhances the auditory startle reflex in rats (D. R. Helton, et al., Psychopharmacology, 113, 205 (1993)). Serotonin 5-HT1A antagonists have been shown to attenuate this nicotine-withdrawal-enhanced startle response (K. Rasmussen, et al., Synapse, 27, 145 (1997); K. Rasmussen, et al., J. Pharmacol. Exp. Ther., 294, 688 (2000)). Thus, 5-HT1A antagonists may find clinical use as a pharmacotherapy for smoking cessation.
In accordance with this invention, there is provided a set of novel compounds, including their enantiomers, which have activity as 5-HT1A agonists and antagonists. Compounds of the present invention are described by the generic formula: 
where:
X is selected from the group consisting of: 
n is selected from the integers 1 through 5;
R1 is C6-C10-aryl or mono or bicyclic heteroaryl, optionally substituted by from 1 to 3 substituents, preferably from 1 to 2 substituents selected from the group of F, Cl, Br, I, xe2x80x94OH, xe2x80x94NH2, CO2H, xe2x80x94CO2xe2x80x94C1-C6 alkyl, xe2x80x94CN, xe2x80x94NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, OR4, and C1-C6 perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole;
R2 is selected from the group consisting of H and C1-C6 alkyl;
R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6;
R4 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, mono or bicyclic heteroaryl, C7-C14 aralkyl, and mono or bicyclic heteroaralkyl, where the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 alkoxy, and C1-C6 perhaloalkoxy;
R5 and R6 are selected independently from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR4; when R5 or R6 are chosen from C3-C6 cycloalkyl or C3-C6 cycloalkenyl, the cyclic group may optionally be substituted at the 1-position with a C1-C3 alkyl group the optical isomers;
and the pharmaceutically acceptable salts thereof
The term C6-C10 aryl includes phenyl and naphthyl. Monocyclic heteroaryl means a 5-6 membered heteroaryl group having from 1-3 heteroatoms selected independently from N, O, and S, such as pyridine, pyrrole, thiophene, furan, imidazole, oxazole, pyrimidmne, pyridazine, pyrazine, thiazole and oxathiazole. Bicyclic heteroaryl includes phenyl fused to a monocyclic 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group fused to another 5-6 membered heteroaryl group, including, but not limited to indole, quinoline, isoquinoline, benzofuran, benzodioxan, benzothiophene, benzimidazole, naphthyridine, and imidazopyridine. The term C7-C14 aralkyl means a C1-C4 alkyl group having a phenyl or naphthyl group as a substituent, and the term heteroaralkyl means a C1-C4 alkyl group having a mono or bicyclic heteroaryl group as defined above as a substituent.
One group of compounds of this invention includes those of the formula: 
wherein R2 and R3 are as defined above and R7 and R8 are each independently selected from H, F, Cl, Br, I, xe2x80x94OH, xe2x80x94NH2, CO2H, xe2x80x94CO2xe2x80x94C1-C6 alkyl, xe2x80x94CN, xe2x80x94NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, OR4, and C1-C6 perhaloalkoxy; or a pharmaceutically acceptable salt thereof.
Another group of compounds of this invention includes those of the formula: 
wherein R2, R3, R7 and R8 are as defined above; or a pharmaceutically acceptable salt thereof.
A further group of compounds of this invention includes those of the formula: 
wherein R2, R3, R7 and R8 are as defined above; or a pharmaceutically acceptable salt thereof.
Within each of these groups described herein is a further subset of compounds wherein R2 is H or C1-C6 alkyl and R3 is xe2x80x94C(O)xe2x80x94C3-C6 cycloalkyl, the cyclalkyl ring of which is optionally substituted at the 1-position with a C1-C3 alkyl group.
Optical isomers of the invention compounds can be selectively synthesized or separated using conventional procedures known to those skilled in the art of organic synthesis.
The pharmaceutically acceptable salts of the invention compounds include the conventional acid addition salts which are formed from an invention compound and a pharmaceutically acceptable organic or inorganic acid. The acid addition salts include, but is not limited to, the acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, dodecylsulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, oxalate, pamoate, pectinate, pivalate, propionate, succinate, tartrate, and tosylate. Also the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, dialkyl sulfates, long chain halides such as lauryl bromide, aralkyl halides like benzyl and phenethyl bromides.
This invention also provides methods of utilizing the compounds of this invention, or a pharmaceutically acceptable salt thereof, in preventing, treating or ameliorating anxiety, generalized anxiety disorder, depression, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer""s Disease, stroke/cerebral ischemia, nausea and vomiting, and in the treatment of prostate cancer. The compounds of this invention can also be used in the treatment, enhancement or facilitation of smoking cessation or in comparable methods of assisting in withdrawal of nicotine-related habits. Each of these methods comprises administering to a mammal in need thereof, preferably a human in need thereof, of a pharmaceutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof.
This invention also provides methods for enhancing the efficacy of selective serotonin reuptake inhibitors (SSRIs) in a mammal, the methods comprising co-administering to a mammal in need thereof pharmaceutically effective amounts of the SSRI in question and a compound of this invention. Among the SSRIs which may be administered in these regimens are fluoxetine hydrochloride, venlafaxine hydrochloride, paroxetine hydrochloride, nefazodone hydrochloride, and sertraline hydrochloride. It will be understood that the SSRIs in these regimens may be administered in dosages and regimens known in the art for these compounds. These methods may also be characterized as methods of treatment of maladies such as depression, anxiety and generalized anxiety disorder in a mammal in need thereof, the methods comprising co-administering to the mammal in need thereof of pharmaceutically effective amounts of a compound of this invention, or a pharmaceutically acceptable salt thereof, and an SSRI.
Compounds in which at least one of R2 and R3 is hydrogen are synthesized in four steps (Scheme 1) starting from cycloalkylalanine which has been protected on the nitrogen atom with the t-butoxycarbonyl group (BOC). This material is coupled to the appropriately substituted aryl heterocycle where X is CH, N, or carbon having a double bond to an adjacent carbon atom using dicyclohexylcarbodiimide (DCC) to afford compound 1. Removal of the BOC group under acidic conditions followed by reduction using a borane complex leads to the penultimate intermediate 2. Subsequent acylation of 2 with the appropriate acid chloride gives compound 3, which is isolated as an acceptable salt. 
Compounds in which both R2 and R3 are other than hydrogen are prepared using two general methods. Reduction of BOC-protected amide 1 with lithium aluminum hydride (LAH) affords methylamine 4 in one step (Scheme 2). Subsequent acylation using the appropriate acid chloride yields N-methylamide 5. 
Alternatively, acylation of intermediate 2 followed by reduction with an appropriate reduction agent such as borane dimethylsulfide gives alkylamine 6, which can then be converted to the final acylated product 7 (Scheme 3). 
Carbamates and ureas can be prepared from the intermediate amines 2, 4, and 6 either by treatment with an appropriate isocyanate or by reacting the amine with a phosgene equivalent such as trichloromethylchloroformate or triphosgene followed by treatment with an appropriate alcohol or amine. Other synthetic procedures may be apparent to those skilled in the art of organic synthesis.